Sulfonamide compounds having 5-HT receptor activity

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which A is methylene or --O--; B is methylene or --O--; g is 0, 1, 2, 3 or 4; U is an alkylene chain optionally substituted by one or more alkyl; Q represents a divalent group containing nitrogen atoms; and T represents an aryl or heteroaryl group, have utility in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson&#39;s disease, obesity, hypertension, Tourette&#39;s syndrome, dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer&#39;s disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress and spasticity ##STR1##

The present invention relates to novel heteroarylsulphonamide compoundswhich have affinity for 5-HT_(1A) and/or D₂ -like (D₂, D₃ and D₄sub-types) receptors, to processes for their preparation, topharmaceutical compositions containing them and to their use in thetreatment of central nervous system disorders, for example depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders,Alzheimer's disease, senile dementia, obsessive-compulsive behaviour,panic attacks, social phobias, eating disorders and anorexia,cardiovascular and cerebrovascular disorders, non-insulin dependentdiabetes mellitus, hyperglycaemia, constipation, arrhythmia, disordersof the neuroendocrine system, stress, and spasticity.

The present invention provides compounds of formula I ##STR2## includingenantiomers and pharmaceutically acceptable salts thereof in which

A is methylene or --O--;

B is methylene or --O--;

g is 0, 1, 2, 3 or 4;

R₁ represents an alkyl group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo; an alkoxy group containing 1 to 3carbon atoms optionally substituted by one or more halo; halo;6,7-methylenedioxy optionally C-substituted by one or two alkyl groupscontaining 1 to 3 carbon atoms; or an alkylthio group containing 1 to 3carbon atoms optionally substituted by one or more halo; thesubstituents represented by R₁ being the same or different when g is 2,3 or 4;

R₂ is H, an alkyl group containing 1 to 3 carbon atoms, or an alkoxygroup containing 1 to 3 carbon atoms;

R₃ and R₄, which are the same or different, are H, or an alkyl groupcontaining 1 to 3 carbon atoms;

U is an alkylene chain containing 1 to 3 carbon atoms, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

Q represents a divalent group of formula IIa, IIb or IIc ##STR3## inwhich V is the group (CH₂)n in which n is 0, 1, 2 or 3, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

V' is an alkylene chain containing 2 to 6 carbon atoms, optionallysubstituted by one or more alkyl groups each containing 1 to 3 carbonatoms;

E is an alkylene chain containing 0 to 2 carbon atoms and E' is analkylene chain containing 1 to 4 carbon atoms provided that the totalnumber of carbon atoms in E and E' amounts to 3 or 4;

R₅ and R₆, which may be the same or different, are H or an alkyl groupcontaining 1 to 4 carbon atoms; and

T represents phenyl, 1- or 2-naphthyl,5-naphth[2,1-d][1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazol, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2-, 3- or4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each ofwhich may be optionally substituted by one or more substituents selectedfrom a) halo, b) an alkyl group containing 1 to 4 carbon atomsoptionally substituted by one or more halo, c) an alkoxy groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, d) an alkylthio group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, e) hydroxy, f) an acyloxy groupcontaining 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) analkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonylgroup containing 2 to 6 carbon atoms, k) a carbamoyl group orcarbamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, I) a sulphamoyl orsulphamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, m) an amino group optionallysubstituted by one or two alkyl groups each containing 1 to 5 carbonatoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido.

In preferred compounds of formula I, A is --O--.

In preferred compounds of formula I, B is --O--.

In more preferred compounds of formula I, both A and B are --O--.

In preferred compounds of formula I, g is 0 or 1. When g is 1, R₁ ispreferably halo or an alkyl group containing 1 to 3 carbon atomsoptionally substituted by one or more halo for example trifluoromethyl.In more preferred compounds of formula I, g is 1 and R₁ is halo. Mostpreferably g is 1 and R₁ is 7-chloro.

In preferred compounds of formula I, R₂ is H.

In preferred compounds of formula I, R₃ and R₄ are both H.

In preferred compounds of formula I, U is methylene.

In preferred compounds of formula I, Q is a group of formula IIc inwhich E and E' are both ethylene, V is methylene, and R₆ is H.

In preferred compounds of formula I, T represents phenyl, 1- or2-naphthyl, 5-naphth[2,1-d][1,2,3]oxadiazolyl, or 2- or 3-pyridyl eachof which may be optionally substituted by one or more substituents,which may be the same or different, selected from an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, nitro, acetamido, halo or an aminogroup optionally substituted by one or two alkyl groups each containing1 to 3 carbon atoms.

In more preferred compounds of formula I, T represents phenyl, 1- or2-naphthyl, 5-naphth[2,1-d][1,2,3]oxadiazolyl, or 2- or 3-pyridyl eachof which may be optionally substituted by one or more substituents,which may be the same or different, selected from methyl, methoxy,trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, nitro,acetamido, halo or an amino group optionally substitued by one or twoalkyl groups each containing 1 to 3 carbon atoms.

In especially preferred compounds of formula I, T is 1-naphthyl,2-naphthyl, 5-naphth[2,1-d][1,2,3]oxadiazolyl, 2-pyridyl, 3-pyridyl,phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl,2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl,2-chlorophenyl, 4-chlorophenyl, 2,5-dibromophenyl, 4-iodophenyl,2,5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl,3,4-dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl,5-chloro-2-methoxyphenyl, 5-fluoro-2-methylphenyl,4-trifluoromethoxyphenyl, 2,5-bis(2,2,2-trifluoroethoxy)phenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-chloro-4-trifluoromethylphenyl, 4-acetamidophenyl, 2-nitrophenyl,3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl,4-methyl-3,5-dinitrophenyl, 5-(diethylamino)-1-naphthyl,2,3-dichlorophenyl or 3-chloro-4-fluorophenyl.

In one group of preferred compounds of formula I, A is --O--, B is--O--, g is 1, R₁ is preferably halo or an alkyl group containing 1 to 3carbon atoms optionally substituted by one or more halo, R₂ is H, R₃ andR₄ are both H, U is methylene, Q is a group of formula IIc in which Eand E' are both ethylene, V is methylene, R₆ is H, and T is 1-naphthyl,2-naphthyl, ⁵ -naphth[2,1-d][1,2,3]oxadiazolyl, 2-pyridyl, 3-pyridyl,phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl,2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl 4-fluorophenyl,2,6-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl,2-chlorophenyl, 4-chlorophenyl, 2,5-dibromophenyl, 4-iodophenyl,2,5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl,3,4-dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl,5-chloro-2-methoxyphenyl, 5-fluoro-2-methylphenyl,4-trifluoromethoxyphenyl, 2,5-bis(2,2,2-trifluoroethoxy)phenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-chloro-4-trifluoromethylphenyl, 4-acetamidophenyl, 2-nitrophenyl,3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl,4-methyl-3,5-dinitrophenyl, 5-(diethylamino)-1-naphthyl,2,3-dichlorophenyl or 3-chloro-4-fluorophenyl.

Compounds of formula I may exist as salts with pharmaceuticallyacceptable acids. Examples of such salts include hydrochlorides,hydrobromides, sulphates, methanesulphonates, nitrates, maleates,acetates, citrates, fumarates, tartrates [eg (+)-tartrates,(-)-tartrates or mixtures thereof including racemic mixtures],succinates, benzoates and salts with amino acids such as glutamic acid.Compounds of formula I and their salts may exist in the form of solvates(for example hydrates).

It will be understood that any group mentioned herein which contains achain of three or more atoms signifies a group in which the chain may bestraight or branched. For example, an alkyl group may comprise propyl,which includes n-propyl and isopropyl, and butyl, which includesn-butyl, sec-butyl, isobutyl and tert-butyl. The term `halo` as usedherein signifies fluoro, chloro, bromo and iodo.

Compounds of formula I and intermediates in their preparation containone or more chiral centres, and exist in different optically activeforms. When compounds of formula I and intermediates in theirpreparation contain one chiral centre, the compounds exist in twoenantiomeric forms and the present invention includes both enantiomersand mixtures of enantiomers. The enantiomers may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallisation; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallisation, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by one ofthe separation procedures described above, a further step is required toliberate the desired enantiomeric form. Alternatively, specificenantiomers may be synthesised by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral centre it mayexist in diastereoisomeric forms. The diastereoisomeric pairs may beseparated by methods known to this skilled in the art, for examplechromatography or crystallisation and the individual enantiomers withineach pair may be separated as described above. The present inventionincludes each diastereoisomer of compounds of formula I and mixturesthereof.

Certain compounds of formula I and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof. Certain compounds of formula I and their salts mayalso exist in the form of solvates, for example hydrates, and thepresent invention includes each solvate and mixtures thereof.

Specific compounds of formula I are:

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamide;

4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-pyridine-sulphonyl)piperidine;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-nitrobenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,4-dimethoxy-benzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzene-sulphonamide;

4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxybenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-chlorobenzene-sulphonamide;

N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamide

N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidylmethyl}-2,3-dichlorobenzensulphonamide

2,3-dichloro-N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4piperidyl]methyl}benzenesulphonamide

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitrobenzenesulphonamide

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamide

2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitrobenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamide;

2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-iodobenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxy-2,3,6-trimethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}naphth[2,1-d][1,2,3]-oxadiazole-5-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4,6-trimethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4,5,6-pentamethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-(diethylamino)-naphthalene-1-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-nitrobenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methyl-3,5-dinitrobenzenesulphonamide;

5-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxybenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-trifluoromethylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethoxybenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-naphthalenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-1-naphthalenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-dimethoxy-benzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methylbenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-fluoro-2-methyl-benzenesulphonamide;

2,5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-nitrobenzene-sulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4-trifluoro-benzenesulphonamide;

2,5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,6-difluorobenzenesulphonamide;

N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;

2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

3-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluoro-benzenesulphonamide;

2,3-dichloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;

4-acetamido-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;

N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-chlorobenzenesulphonamide;

N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamide;

3-chloro-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide;

2,3-dichloro-N-{[1-(6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;

and pharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates, or other mixtures

Specific enantiomers.

Specific enantiomeric forms of compounds of formula I include:

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamide;

(S)-4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-pyridinesulphonyl)-piperidine);

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-nitrobenzene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,4-dimethoxy-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluoro-benzenesulphonamide;

(S)-4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxybenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluoro-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-chloro-benzenesulphonamide;

(S)-N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-pyridine-2-sulphonamide

(S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamide

(S)-2,3-dichloro-N-{(1-7-(trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}benzenesulphonamide

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitro-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamide;

(S)-2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-iodobenzene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxy-2,3,6-trimethylbenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}naphth[2,1-d][1,2,3]oxadiazole-5-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4,6-trimethyl-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4,5,6-pentamethylbenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-(diethyl-amino)naphthalene-1-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoro-methylbenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-nitrobenzene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methyl-3,5-dinitrobenzenesulphonamide;

(S)-5-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxybenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-trifluoro-methylbenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoro-methoxybenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-naphthalene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-1-naphthalene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-dimethoxy-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methyl-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzene-sulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-fluoro-2-methylbenzenesulphonamide;

(S)-2,5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-nitro-benzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4-trifluoro-benzenesulphonamide;

(S)-2,5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,6-difluorobenzenesulphonamide;

(S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;

(S)-2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;

(S)-3-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluoro-benzenesulphonamide;

(S)-2,3-dichloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

(S)-4-acetamido-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;

(S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;

(S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-chlorobenzenesulphonamide;

(S)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamide;

(S)-3-chloro-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide;

(S)-2,3-dichloro-N-{[1-(6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;

and pharmaceutically acceptable salts thereof.

A particularly preferred compound isN-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamideincluding enantiomers and pharmaceutically acceptable salts thereof.

It will be appreciated by those skilled in the art that the term"1,4-benzodioxan" as used in the above lists and throughout thisspecification is synonymous with the term "2,3-dihydro-1,4-benzodioxin".

The present invention also includes pharmaceutical compositionscontaining a therapeutically effective amount of a compound of formula Ior a salt thereof together with a pharmaceutically acceptable diluent orcarrier.

As used hereinafter, the term "active compound" denotes a compound offormula I or a salt thereof. In therapeutic use, the active compound maybe administered orally, rectally, parenterally or topically, preferablyorally. Thus the therapeutic compositions of the present invention maytake the form of any of the known pharmaceutical compositions for oral,rectal, parenteral or topical administration. Pharmaceuticallyacceptable carriers suitable for use in such compositions are well knownin the art of pharmacy. The compositions of the invention may contain0.1-99% by weight of active compound. The compositions of the inventionare generally prepared in unit dosage form. Preferably the unit dosageof active ingredient is 1-500 mg. The excipients used in the preparationof these compositions are the excipients known in the pharmacist's art.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, syrups and aqueous or oilsuspensions. The excipients used in the preparation of thesecompositions are the excipients known in the pharmacist's art. Tabletsmay be prepared by mixing the active compound with an inert diluent suchas calcium phosphate in the presence of disintegrating agents, forexample maize starch, and lubricating agents, for example magnesiumstearate, and tableting the mixture by known methods. The tablets may beformulated in a manner known to those skilled in the art so as to give asustained release of the compounds of the present invention. Suchtablets may, if desired, be provided with enteric coatings by knownmethods, for example by the use of cellulose acetate phthalate.Similarly, capsules, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, may beprepared by conventional means and, if desired, provided with entericcoatings in a known manner. The tablets and capsules may convenientlyeach contain 1 to 500 mg of the active compound. Other compositions fororal administration include, for example, aqueous suspensions containingthe active compound in an aqueous medium in the presence of a non-toxicsuspending agent such as sodium carboxymethylcellulose, and oilysuspensions containing a compound of the present invention in a suitablevegetable oil, for example arachis oil.

The active compound may be formulated into granules with or withoutadditional excipients. The granules may be ingested directly by thepatient or they may be added to a suitable liquid carrier (for examplewater) before ingestion. The granules may contain disintegrants (forexample a pharmaceutically acceptable effervescent couple formed from anacid and a carbonate or bicarbonate salt) to facilitate dispersion inthe liquid medium.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for example,suppositories with cocoa butter or polyethylene glycol bases.

Pharmaceutical compositions may also be administered parenterally (forexample subcutaneously, intramuscularly, intradermally and/orintravenously [such as by injection and/or infusion]) in the knownpharmaceutical dosage forms for parenteral administration (for examplesterile suspensions in aqueous and/or oily media and/or sterilesolutions in suitable solvents, preferably isotonic with the blood ofthe intended patient). Parenteral dosage forms may be sterilised (forexample by micro-filtration and/or using suitable sterilising agents[such as ethylene oxide]). Optionally one or more of the followingpharmaceutically acceptable adjuvants suitable for parenteraladministration may be added to parenteral dosage forms: localanaesthetics, preservatives, buffering agents and/or mixtures thereof.Parenteral dosage forms may be stored in suitable sterile sealedcontainers (for example ampoules and/or vials) until use. To enhancestability during storage the parenteral dosage form may be frozen afterfilling the container and fluid (for example water) may be removed underreduced pressure.

Pharmaceutical compositions may be administered nasally in knownpharmaceutical forms for such administration (for example sprays,aerosols, nebulised solutions and/or powders). Metered dose systemsknown to those skilled in the art (for example aerosols and/or inhalers)may be used.

Pharmaceutical compositions may be administered to the buccal cavity(for example sub-lingually) in known pharmaceutical forms for suchadministration (for example slow dissolving tablets, chewing gums,troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/orpowders).

Compositions for topical administration may comprise a matrix in whichthe pharmacologically active compounds of the present invention aredispersed so that the compounds are held in contact with the skin inorder to administer the compounds transdermally. A suitable transdermalcomposition may be prepared by mixing the pharmaceutically activecompound with a topical vehicle, such as a mineral oil, petrolatumand/or a wax, for example paraffin wax or beeswax, together with apotential transdermal accelerant such as dimethyl sulphoxide orpropylene glycol. Alternatively the active compounds may be dispersed ina pharmaceutically acceptable cream or ointment base. The amount ofactive compound contained in a topical formulation should be such that atherapeutically effective amount of the compound is delivered during theperiod of time for which the topical formulation is intended to be onthe skin.

The compounds of the present invention may also be administered bycontinuous infusion either from an external source, for example byintravenous infusion or from a source of the compound placed within thebody. Internal sources include implanted reservoirs containing thecompound to be infused which is continuously released for example byosmosis and implants which may be (a) liquid such as a suspension orsolution in a pharmaceutically acceptable oil of the compound to beinfused for example in the form of a very sparingly water-solublederivative such as a dodecanoate salt or ester or (b) solid in the formof an implanted support, for example of a synthetic resin or waxymaterial, for the compound to be infused. The support may be a singlebody containing all the compound or a series of several bodies eachcontaining part of the compound to be delivered. The amount of activecompound present in an internal source should be such that atherapeutically effective amount of the compound is delivered over along period of time.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients.

The present invention also comprises the use of a compound of formula Ias a medicament.

The compounds of formula I or salts thereof or pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof formula I or a salt thereof may be used to treat depression, anxiety,psychoses (for example schizophrenia), tardive dyskinesia, Parkinson'sdisease, obesity, hypertension, Tourette's syndrome, sexual dysfunction,drug addiction, drug abuse, cognitive disorders, Alzheimer's disease,senile dementia, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders, anorexia, cardiovascular and cerebrovasculardisorders, non-insulin dependent diabetes mellitus, hyperglycaemia,constipation, arrhythmia, disorders of the neuroendocrine system,stress, and spasticity in human beings. Whilst the precise amount ofactive compound administered in such treatment will depend on a numberof factors, for example the age of the patient, the severity of thecondition and the past medical history and always lies within the sounddiscretion of the administering physician, the amount of active compoundadministered per day is in the range 1 to 1000 mg preferably 5 to 500 mggiven in single or divided doses at one or more times during the day.

A further aspect of the present invention provides the use of a compoundof formula I in the manufacture of a medicament for treating depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders,Alzheimer's disease, senile dementia, obsessive-compulsive behaviour,panic attacks, social phobias, eating disorders and anorexia,cardiovascular and cerebrovascular disorders, non-insulin dependentdiabetes mellitus, hyperglycaemia, constipation, arrhythmia, disordersof the neuroendocrine system, stress, or spasticity in human beings.

The present invention also provides a method of treating depression,anxiety, psychoses (for example schizophrenia), tardive dyskinesia,Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexualdysfunction, drug addiction, drug abuse, cognitive disorders,Alzheimer's disease, senile dementia, obsessive-compulsive behaviour,panic attacks, social phobias, eating disorders and anorexia,cardiovascular and cerebrovascular disorders, non-insulin dependentdiabetes mellitus, hyperglycaemia, constipation, arrhythmia, disordersof the neuroendocrine system, stress, or spasticity in human beingswhich comprises the administration of a therapeutically effective amountof a compound of formula I to a patient in need thereof.

Processes for the preparation of compounds of formula I will now bedescribed. These processes form a further aspect of the presentinvention. The processes are preferably carried out at atmosphericpressure, at a temperature in the range 0-200° C., preferably in therange 20-150° C. The substituents are as defined for formula I aboveunless otherwise stated.

Compounds of formula I in which Q is a group of formula IIa in which R₅is H and V is (CH₂)_(n) wherein n is 1,2 or 3, may be prepared byreaction of a compound of formula III ##STR4## in which m is 0, 1 or 2,with a compound of formula IV ##STR5## in which Z is a leaving group,for example toluene-4-sulphonyloxy, optionally in the presence of asuitable solvent, for example acetonitrile, optionally in the presenceof a base, for example potassium carbonate, and optionally in thepresence of a catalyst, for example potassium iodide.

Compounds of formula III may be prepared by reaction of a compound offormula V ##STR6## in which D is a protecting group, for examplebenzylidene, with a sulphonylating agent of formula X--SO₂ --T in whichX is a leaving group, for example halo or hydroxy in the presence of abase, for example triethylamine, in a suitable solvent, for exampledichloromethane, followed by removal of the protecting group, forexample by acid-catalysed hydrolysis.

Compounds of formula IV in which Z is toluene-4-sulphonyloxy, may beprepared by reaction of a compound of formula VI ##STR7## withtoluene-4-sulphonyl chloride, optionally in the presence of a base, forexample pyridine.

Compounds of formula VI in which A and B are both --O--, U is methylene,and R₂, R₃ and R₄ are all H, may be prepared by cyclisation of acompound of formula VII ##STR8## in which R is H or an alkyl groupcontaining 1 to 4 carbon atoms, using a base, for example potassiumcarbonate.

Compounds of formula VII may be prepared by oxidation of a compound offormula VIII ##STR9## in which R is H or an alkyl group containing 1 to4 carbon atoms, with a peroxyacid, for example 3-chloroperoxybenzoicacid.

Compounds of formula VII may be prepared by alkylating a compound offormula IX ##STR10## in which R is H or an alkyl group containing 1 to 4carbon atoms, with a compound of formula X ##STR11## in which Z is aleaving group, for example chloro or toluene-4-sulphonyloxy, in asuitable solvent, for example dimethylformamide, in the presence of abase, for example potassium carbonate. When the appropriateenantiomerically pure form of a compound of formula X, for example(R)-glycidyl 4-toluenesulphonate, is used, the single (S)-enantiomer ofa compound of formula VI can be prepared.

Compounds of formula I in which U is methylene and Q is a group offormula IIa in which R₅ is H and V is (CH₂)_(n) wherein n is 1, 2 or 3,may be prepared by reaction of a compound of formula XI ##STR12## with acompound of formula III, followed by reduction of the intermediate iminewith a suitable reducing agent, for example, sodium borohydride.

Compounds of formula XI may be prepared by oxidation of a compound offormula VI in which U is methylene, with a suitable oxidising agent, forexample pyridinium chlorochromate.

Compounds of formula I in which Q is a group of formula IIb may beprepared by reaction of a compound of formula XII ##STR13## in which D'is H, with a compound of formula IV in which Z is a leaving group, forexample toluene-4-sulphonyloxy, optionally in the presence of a base,for example potassium carbonate, optionally in the presence of asuitable solvent, for example acetonitrile, and optionally in thepresence of a catalyst, for example potassium iodide.

Compounds of formula XII in which D' is H may be prepared bydeprotection of a compound of formula XII in which D' is a protectinggroup, for example tert-butoxycarbonyl, for example by hydrolysis in thepresence of an acid, for example trifluoroacetic acid.

Compounds of formula XII in which D' is a protecting group may beprepared by reaction of a compound of formula XIII ##STR14## in which D'is a protecting group, for example tert-butoxycarbonyl, with a compoundof formula X--SO₂ --T in which X is a leaving group, for example halo orhydroxy, in the presence of a base, for example triethylamine in asuitable solvent such as dichloromethane.

Compounds of formula I in which Q is a group of formula IIc in which Vis (CH₂)_(n) wherein n is 1, 2 or 3, may be prepared by reaction of acompound of formula XIV ##STR15## in which D' is H and m is 0, 1 or 2,with a compound of formula IV in which Z is a leaving group, for exampletoluene-4-sulphonyloxy, optionally in the presence of a base, forexample potassium carbonate, optionally in the presence of a suitablesolvent, for example acetonitrile, and optionally in the presence of acatalyst, for example potassium iodide.

Compounds of formula XIV in which D' is H may be prepared bydeprotection of a compound of formula XIV in which D' is a protectinggroup, for example tert-butoxycarbonyl, for example by hydrolysis in thepresence of an acid, for example trifluoroacetic acid.

Compounds of formula XIV in which D' is a protecting group may beprepared by reaction of a compound of formula XV ##STR16## in which D'is a protecting group, for example tert-butoxycarbonyl, and m is 0, 1 or2, with a compound of formula X--SO₂ --T in which X is a leaving group,for example halo or hydroxy, in the presence of a base, for exampletriethylamine in a suitable solvent such as dichloromethane.

Compounds of formula I in which Q is a group of formula IIc may also beprepared by reaction of a compound of formula XVI ##STR17## with asulphonylating agent of formula X--SO₂ --T in which X is a leavinggroup, for example halo or hydroxy, in the presence of a base, forexample triethylamine, in a suitable solvent, for exampledichloromethane.

Compounds of formula XVI in which R₆ is H may be prepared from compoundsof formula XVII ##STR18## in which D is a protecting group, for example5-bromo-2-hydroxybenzylidene, by acid or base catalysed hydrolysis.

Compounds of formula XVII may be prepared by reaction of a compound offormula XVIII ##STR19## in which D is a protecting group, for example5-bromo-2-hydroxybenzylidene with a compound of formula IV, optionallyin the presence of a base, for example triethylamine.

Compounds of formula XVIII may be prepared by reaction of a compound offormula XIX ##STR20## with a protecting reagent, for example5-bromo-2-hydroxybenzaldehyde.

Compounds of formula I in which R₅ is an alkyl group may also beprepared by alkylation of a compound of formula I in which R₅ is H with,for example, formaldehyde and formic acid, or an aldehyde and a reducingagent such as sodium cyanoborohydride.

The ability of compounds of formula I to interact with5-hydroxytryptamine (5-HT) receptors has been demonstrated by thefollowing test which determines the ability of the compounds to inhibittritiated ligand binding to 5-HT receptors in vitro and in particular to5-HT_(1A) receptors.

Hippocampal tissue from the brains of male Charles River CD ratsweighing between 150-250 g were homogenised in ice-cold 50 mM Tris-HClbuffer (pH 7.7) when measured at 25° C., 1:40 w/v) and centrifuged at30,000 g at 4° C. for 10 minutes. The pellet was rehomogenised in thesame buffer, incubated at 37° C. for 10 minutes and centrifuged at30,000 g at 4° C. for 10 minutes. The final pellet was resuspended in 50mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl₂, 0.1% L-ascorbic acidand 10 μM pargyline hydrochloride (equivalent to 6.25 mg wet weight oftissue/ml) and used immediately in the binding assay. Aliquots (400 μl;equivalent to 2.5 mg wet weight of tissue/tube) of this suspension wereadded to tubes containing the ligand (50 μl; 2 nM) and distilled water(50 μl; total binding) or 5-HT (50 μl; 10 μM; non-specific binding) ortest compound (50 μl; at a single concentration of 10⁻⁶ M or at 10concentrations ranging from 10⁻¹¹ -10⁻³ M). The ligand was [³H]8-hydroxy-2-(dipropylamino)tetralin ([³ H]8-OH-DPAT) and the mixturewas incubated at 25° C. for 30 minutes before the incubation wasterminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Thefilters were punched out into vials, scintillation fluid added andradioactivity determined by liquid scintillation counting. Thepercentage displacement of specific binding of the tritiated ligand wascalculated for the single concentration (10⁻⁶ M) of test compound.Displacement curves were then produced for those compounds whichdisplaced ≧50% of specific binding of the tritiated ligand at 10⁻⁶ Musing a range of concentrations of the compound. The concentration whichgave 50% inhibition of specific binding (IC₅₀) was obtained from thecurve. The inhibition coefficient Ki was then calculated using theformula ##EQU1## in which [ligand] is the concentration of the tritiatedligand used and K_(D) Is the equilibrium dissociation constant for theligand.

The ability of compounds of formula I to interact with dopaminereceptors has been demonstrated by the following test which determinesthe ability of the compounds to inhibit tritiated ligand binding todopamine receptors in vitro and in particular to the D₂ -like dopaminereceptors.

Striatal tissue from the brains of male Charles River CD rats weighingbetween 140-250 g were homogenised in ice-cold 50 mM Tris-HCl buffer (pH7.7 when measured at 25° C.) and centrifuged at 40,000 g for 10 minutes.The pellet was resuspended in Tris salts buffer (50 mM Tris-HCl buffercontaining 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂ and 1 mM MgCl₂ with theaddition of 6 mM ascorbic acid; pH 7.7 when measured at 25° C.), andagain centrifuged at 40,000 g for 10 minutes. The final pellet wasstored at -80° C. Before each test the pellet was resuspended in Trissalts buffer (equivalent to 2 mg wet weight of tissue/ml). Aliquots (720μl; equivalent to 1.44 mg wet weight of tissue/tube) of this suspensionwere then added to tubes containing the ligand (40 μl; 1 nM) and Trissalts buffer (40 μl; total binding) or spiroperidol (40 μl; 10 nM;non-specific binding) or test compound (40 μl; at a single concentrationof 10⁻⁶ M or at 6 concentrations ranging from 10⁻¹¹ -10⁻⁴ M). The ligandwas tritiated (S)-sulpiride and the mixture was incubated at 4° C. for40 minutes before the incubation was terminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Thefilters were punched out in to vials, scintillation fluid added and wereleft for about 20 hours before being counted by scintillationspectrophotometry. The percentage displacement of specific binding ofthe tritiated ligand was calculated for the single concentration (10⁻⁶M) of test compound. Displacement curves were then produced over a rangeof concentrations for those compounds which displaced ≧50% of specificbinding of the tritiated ligand at 10⁻⁶ M. The concentration which gavea 50% inhibition of specific binding (IC50) was obtained from the curve.The inhibition coefficient Ki was then calculated using the formula##EQU2## in which [ligand] is the concentration of the tritiated ligandused and K_(D) is the equilibrium dissociation constant for the ligand.

The K_(i) values obtained in the above tests for 5-HT_(1A), and D₂ -likebinding for each of the final products of the Examples hereinafter aregiven in Table I below.

                  TABLE 1                                                         ______________________________________                                                        Ki (nM) value for                                             Example Number    5-HT.sub.1A                                                                           D.sub.2 -like                                       ______________________________________                                         1                  86.8    29.4                                                 2   11.4   27.9                                                               3   31.6  28                                                                  4 15 105                                                                      5 37   69.8                                                                   6 20   40.2                                                                   7 35   37.8                                                                   8 45   37.2                                                                   9 42   96.4                                                                  10   7.4   50.1                                                               11 69 157                                                                     12 30   28.7                                                                  13 20 102                                                                     14 25 111                                                                     15    82% 212                                                                 16    84% 258                                                                 17    88% 519                                                                 18    90% 227                                                                 19    55% 306                                                                 20    75% 235                                                                 21    71% 249                                                                 22    59% 317                                                                 23    82%     83%                                                             24    90% 533                                                                 25    91% 119                                                                 26    88%     87%                                                             27    68% 351                                                                 28    68% 352                                                                 29    67% 357                                                                 30    65% 241                                                                 31    60% 215                                                                 32    87% 285                                                                 33    91% 301                                                                 34    87%  88                                                                 35    81% 328                                                                 36    68% 487                                                                 37    87%  85                                                                 38    95% 330                                                                 39    98% 438                                                                 40    93%    107%                                                             41    93%    106%                                                             42    80%     84%                                                             43   1.5  73                                                                  44 14  23                                                                     45    97%    109%                                                             46    96%    106%                                                             47 16  48                                                                     48    88%    103%                                                             49    77%     89%                                                           ______________________________________                                         The % figures in Table 1 are for % displacement at 10.sup.-6 M.          

Advantageous compounds of the present invention have a Ki of less than100 nM for 5-HT_(1A) or a binding affinity for 5-HT_(1A) of greater than90% at 10⁻⁶ M and a Ki of less than 100 nM for D₂ -like receptors or abinding affinity for D₂ -like receptors of greater than 90% at 10⁻⁶ M.

The invention is illustrated by the following Examples which are givenby way of example only. The final products of the Examples werecharacterised by one or more of the following procedures: gas-liquidchromatography; high performance liquid chromatography; elementalanalysis, nuclear magnetic resonance spectroscopy and infraredspectroscopy.

EXAMPLE 1

Pyridine (1.85 ml) was added to a stirred solution of4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (4.46 g) andpyridine-2-sulphonyl chloride (3.7 g) in dichloromethane (110 ml) at-10° C. under a nitrogen atmosphere. The reaction was then warmed toambient temperature over 16 hours and poured into water (300 ml). Theorganic layer was separated and further washed with hydrochloric acid (1M, 2×200 ml), saturated aqueous sodium bicarbonate solution (200 ml) andbrine (200 ml). After drying over anhydrous magnesium sulphate, thesolution was evaporated to dryness to affordN-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide(3.5 g) as an oil.

Trifluoroacetic acid (12.5 ml) was added to a solution of the productfrom the previous reaction (2.0 g) in dichloromethane (12.5 ml) and themixture stirred at ambient temperature for 4 hours. The solvent wasremoved under reduced pressure to yield crudeN-4-piperidylmethyl)pyridine-2-sulphonamide trifluoroacetate.

A stirred mixture of this material,(R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (1.77 g,prepared as described in WO97/03071), potassium carbonate (7.6 g), andpotassium iodide (10 mg) in acetonitrile (150 ml) was heated at reflux,under nitrogen, for 60 hours. The reaction was cooled, filtered andconcentrated under reduced pressure to afford a brown viscous oil (5.8g) which was purified by flash chromatography on silica gel eluting withneat ethyl acetate. The appropriate fractions were combined and thesolvent removed under reduced pressure to give a colourless oil (0.6 g).Hydrogen chloride gas was bubbled through a solution of the oil in amixture of dichloromethane (10 ml) and diethyl ether (20 ml), until pH 1was achieved. The solvent was removed under reduced pressure and theresulting hygroscopic yellow gum was immediately dried at 80° C. underreduced pressure to afford(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamidemonohydrochloride 0.6 hydrate as a cream solid foam (0.5 g); m.p. 143°C. (dec.), [α]_(D) ²³ -51.6° (c=1.03, MeOH).

EXAMPLE 2

Triethylamine (6.3 ml) was added to a cloudy solution ofN-benzylidene-4-piperidylmethylamine (4.05 g) and pyridine-2-sulphonylchloride (4.0 g) in dichloromethane (100 ml) and the resulting clearyellow solution was stirred for 14 hours. Removal of the solvent underreduced pressure gave a yellow solid which on addition of diethyl ether(100 ml) partly dissolved. The insoluble white solid (triethylaminehydrochloride) was removed by filtration. Evaporation of the filtrateafforded a flocculent yellow solid which recrystallised from ethanol togive 4-[N-(benzylidene)aminomethyl]-1-(2-pyridinesulphonyl)piperidine asa white crystalline solid (4.7 g).

A solution of the product from the previous reaction (4.5 g) andpotassium hydrogen sulphonate (8.76 g) in water (110 ml) was stirred for20 hours. The reaction was washed with diethyl ether (3×100 ml),basified to pH 14 using aqueous sodium hydroxide solution (5 M) andextracted with diethyl ether (4×100 ml). These latter ethereal layerswere combined, dried over anhydrous magnesium sulphate and evaporated todryness to give crude 4-(aminomethyl)-1-(2-pyridinesulphonyl)piperidineas a yellow oil (2.7 g).

A stirred mixture of this material,(R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate, potassiumcarbonate (2.73 g) and potassium iodide (10 mg) in acetonitrile (125 ml)was heated at reflux, under nitrogen, for 20 hours. The reaction wascooled and stirred at ambient temperature for a further 24 hours. Excesspotassium carbonate was removed by filtration and the filtrateconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with a 19:1 mixture of ethylacetate and methanol afforded a yellow oil (2.1 g). Trituration withdiethyl ether (50 ml) gave(S)-(-)-4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2-pyridinesulphonyl)piperidine0.8 hydrate as an off-white solid (1.68 g); m.p. 71-74° C., [α]_(D) ²²-40.9° (c=0.33, MeOH).

EXAMPLE 3

Triethylamine (2.4 ml) was added to an orange solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(1.67 g, prepared as described in WO97/03071) and pyridine-3-sulphonylchloride (2.0 g) in dichloromethane (60 ml) under nitrogen and thesolution stirred for 3 hours. The reaction was concentrated underreduced pressure then purified by flash chromatography on silica geleluting with a 9:1 mixture of dichloromethane and methanol to give anorange oil (2.0 g). Trituration with hot diethyl ether afforded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-sulphonamide0.8 hydrate as a pale pink solid (1.2 g); m.p. 127-128° C., [α]_(D) ²²-38.5° (c=1.02, MeOH).

EXAMPLE 4

Triethylamine (0.62 ml) was added to a cloudy solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 9) and 4-nitrobenzenesulphonyl chloride (0.65 g) indichloromethane (22 ml) under nitrogen. The resulting solution wasstirred for 3 hours then left to stand for 14 hours. The reaction wasdiluted with dichloromethane (100 ml), washed with water (100 ml) andbrine (100 ml), dried over anhydrous magnesium sulphate and concentratedunder reduced pressure to afford an orange oil (0.95 g). Purification byflash chromatography on silica gel eluting with a 19:1 mixture ofdichloromethane and methanol gave(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-4-nitrobenzenesulphonamideas a light brown solid (0.5 g); m.p. 147-148° C., [α]_(D) ²².5 -23.5°(c=1.01, CH₂ Cl₂).

EXAMPLE 5

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 4-fluorobenzenesulphonyl chloride (0.65 g) indichloromethane (22 ml) under nitrogen and stirred for 3 hours. Thereaction was left to stand for 14 hours then diluted withdichloromethane (100 ml), washed with water (100 ml) and brine (100 ml),dried over anhydrous magnesium sulphate and concentrated under reducedpressure. Purification by flash chromatography on silica gel elutingwith a 19:1 mixture of dichloromethane and methanol gave a yellow oilwhich on trituration with diethyl ether yielded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamideas a yellow solid (0.4 g); m.p. 127-129° C., [α]_(D) ²² -41.3° (c=0.72,MeOH).

EXAMPLE 6

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 3,4-dimethoxybenzene-sulphonyl chloride (0.65 g) indichloromethane (22 ml) under nitrogen. The reaction was stirred for 3hours then left to stand for 14 hours prior to the addition ofdichloromethane (100 ml). The solution was then washed with water (2×30ml) and brine (2×50 ml), dried over anhydrous magnesium sulphate andconcentrated under reduced pressure to afford a brown oil. Purificationby flash chromatography on silica gel eluting with a 40:1 mixture ofdichloromethane and methanol gave a colourless oil (0.48 g) whichcrystallised on standing. Trituration with diethyl ether yielded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,4-dimethoxybenzenesulphonamide as a white solid (0.3 g);m.p. 99-101° C., [α]_(D) ²³ -41.0° (c=0.52, MeOH).

EXAMPLE 7

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 2,4-difluorobenzene-sulphonyl chloride (0.62 g) indichloromethane (22 ml) under nitrogen. The reaction was stirred for 3hours then left to stand for 14 hours. Dichloromethane (100 ml) wasadded and the reaction was washed with water (2×30 ml) and brine (2×50ml). The mixture was dried over anhydrous magnesium sulphate andconcentrated under reduced pressure to afford a brown oil. Purificationby flash chromatography on silica gel eluting with a 40:1 mixture ofdichloromethane and methanol gave a yellow oil (0.30 g). Triturationwith diethyl ether yielded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamideas a beige solid (0.14 g); m.p. 119-121 ° C., [α]_(D) ²³ -41.4° (c=0.16,MeOH).

EXAMPLE 8

Triethylamine (0.62 ml) was added to a cloudy solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 4-acetamidobenzenesulphonyl chloride (0.65 g) indichloromethane (22 ml) under nitrogen. The resulting solution wasstirred for 20 hours, diluted with dichloromethane (100 ml) and washedwith water (100 ml) and brine (100 ml). After drying over anhydrousmagnesium sulphate, the mixture was concentrated under reduced pressureto afford an orange oil. Purification by flash chromatography on silicagel eluting with a 15:1 mixture of dichloromethane and methanol gave anorange gum. Trituration with diethyl ether (20 ml) yielded(S)-(-)-4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamideas a pale orange solid (0.34 g); m.p. 173-176° C., [α]_(D) ²² -39.3°(c=0.37, MeOH).

EXAMPLE 9

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 4-methoxybenzene-sulphonyl chloride (0.61 g) indichloromethane (22 ml) under nitrogen. The reaction was stirred for 20hours, diluted with dichloromethane (100 ml) and washed with water (100ml) and brine (100 ml). After drying over anhydrous magnesium sulphate,the mixture was concentrated under reduced pressure to afford an orangeoil. Purification by flash chromatography on silica gel eluting with a20:1 mixture of dichloromethane and methanol gave a colourless gum.Trituration with diethyl ether (20 ml) yielded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]-methyl}-4-methoxybenzenesulphonamideas a white solid (0.20 g); m.p. 130-131° C., [α]_(D) ²².5 28.9° (c=0.51,CH₂ Cl₂).

EXAMPLE 10

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 2,6-difluorobenzene-sulphonyl chloride (0.62 g) indichloromethane (22 ml), under nitrogen, and stirred for 20 hours. Thereaction was diluted with dichloromethane (100 ml), washed with water(100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate andconcentrated under reduced pressure to afford an orange oil.Purification by flash chromatography on silica gel eluting with a 20:1mixture of dichloromethane and methanol gave an orange gum. Triturationwith petroleum ether (b.p. 40-60° C.) yielded(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzenesulphonamideas an off-white solid (0.29 g); m.p. 122-124° C., [α]_(D) ²².5 -22.1°(c=1.0, CH₂ Cl₂).

EXAMPLE 11

Triethylamine (0.62 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine(0.44 g) and 4-chlorobenzene-sulphonyl chloride (0.62 g) indichloromethane (22 ml), under nitrogen, and stirred for 20 hours. Thereaction was diluted with dichloromethane (100 ml), washed with water(100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate andconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with a 20:1 mixture ofdichloromethane and methanol gave(S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-chlorobenzene-sulphonamideas a white solid (0.30 g); m.p. 152-154° C., [α]_(D) ²².5 -23.8°(c=0.97, CH₂ Cl₂).

EXAMPLE 12

Trifluoroacetic acid (10 ml) was added to a solution ofN-{[1-(tert-butoxycarbonyl)-4-piperidyl]methyl}pyridine-2-sulphonamide(1.45 g) in dichloromethane (10 ml) and the mixture stirred at ambienttemperature for 1.5 hours. The solvent was removed under reducedpressure to yield crude N-(4-piperidyl methyl)pyridine-2-sulphonamidetrifluoroacetate.

A mixture of this material,(R)-7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate(1.0 g), potassium carbonate (3.6 g), and potassium iodide (10 mg) inacetonitrile (130 ml) was heated at reflux, with stirring, undernitrogen for 24 hours. The reaction was cooled, filtered andconcentrated under reduced pressure to afford a brown viscous oil.Purification was effected by flash chromatography on silica gel elutingwith a 95:5 mixture of dichloromethane and methanol. The appropriatefractions were combined and the solvent removed under reduced

pressure to give a yellow oil (1.0 g) which contained some impurities.The oil was dissolved in ethyl acetate (100 ml) and the solutionextracted with dilute hydrochloric acid (5 M; 3×300 ml). The aqueousphase was basified to pH 14 by the addition of dilute aqueous sodiumhydroxide solution (5 M) and the product was extracted into ethylacetate (3×100 ml). The organic extracts were combined, dried overanhydrous magnesium sulphate and evaporated to dryness to give a clearoil that was triturated with diethyl ether (10 ml) to afford(S)-(-)-N-J[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl,pyridine-2-sulphonamide(0.22 g) m.p. 138-140 ° C., [α]_(D) ²¹ -44.7° (c=0.483, MeOH).

EXAMPLE 13

A mixture of (R)-7-bromo-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate(6.5 g, prepared as described in WO97/03071),N-benzylidene-4-piperidylmethylamine (3.0 g), potassium carbonate (4.1g), and potassium iodide (10 mg) in acetonitrile (200 ml) was heated atreflux, with stirring, under nitrogen for 24 hours. The reaction wascooled, filtered and concentrated under reduced pressure to afford(S)-N-benzylidene-1-[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine(6.3 g) as an orange-brown viscous oil.

The crude product from the previous reaction (6.3 g) was stirred inaqueous potassium hydrogen sulphate solution (0.6 M; 125 ml) for threehours at ambient temperature. The solution was washed with ether (3×200ml), basified using aqueous sodium hydroxide solution (5 M) thenextracted with ether (3×200 ml). The combined ethereal layers werewashed with water (200 ml), dried over magnesium sulphate and evaporatedto dryness to afford(S)-4-(aminomethyl)-1-(7-bromo-1,4-benzodioxan-2-ylmethyl)piperidine(4.0 g) as a brown oil.

Triethylamine (0.63 ml) was added to a solution of(S)-4-(aminomethyl)-1-(7-bromo-1,4-benzodioxan-2-ylmethyl)piperidine(0.5 g) and 2,3-dichlorobenzenesulphonyl chloride (0.74 g) indichloromethane (15 ml) and stirred under nitrogen for 24 hours. Thereaction was diluted with dichloromethane (100 ml), washed with water(100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate andconcentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with a 9:1 mixture ofdichloromethane and methanol gave(S)-(-)-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamideas a cream solid (0.8 g) m.p. 93-95° C., [α]_(D) ²² -37.1°(c=0.93,MeOH).

EXAMPLE 14

Hexamethylenetetramine (47.5 g) was added portionwise to a stirredsolution of 4-trifluoromethylphenol (50 g) in trifluoroacetic acid (680ml) and the mixture was heated at reflux temperature for 24 hours. Aftercooling, water (355 ml) was added followed by aqueous sulphuric acid(50% v/v, 190 ml) and the reaction was stirred at ambient temperaturefor 4 hours. The acidic aqueous phase was extracted with diethyl ether(3×500 ml). The combined organic extracts were washed with hydrochloricacid (5M, 3×500 ml) then water (500 ml) and dried over magnesiumsulphate. The solvent was removed under reduced pressure and the residuepurified by column chromatography on silica eluting with a 4:1 mixtureof petroleum ether (b.p. 40-60° C.) and ethyl acetate. The appropriatefractions were combined and the solvent removed under reduced pressureto give 5-trifluoromethyl-2-hydroxybenzaldehyde (25 g) as a light pinksolid.

A mixture of (R)-glycidyl 4-toluenesulphonate (24 g),5-trifluoromethyl-2-hydroxybenzaldehyde (20 g) and potassium carbonate(16 g) in dimethylformamide (550 ml) was stirred and heated at 60° C.for 72 hours. After cooling, brine (1.5 L) was added and the resultantmixture extracted with ether (4×500 ml). The combined ether extractswere washed with brine (2×500 ml), then water (500 ml) and dried overmagnesium sulphate. The residue was purified by flash columnchromatography on silica eluting with a 3:1 mixture of petroleum ether(b.p. 40-60 ° C.) and ethyl acetate to give(R)-5-trifluoromethyl-2-(2,3-epoxypropoxy)benzaldehyde (18.7 g) as ayellow oil.

A mixture of the product from the previous reaction (18.7 g) and3-chloroperoxybenzoic acid (57-86%, 48.7 g) in dichloromethane (1L) washeated under reflux for 24 hours then allowed to cool to ambienttemperature. The mixture was washed with saturated aqueous sodiumbicarbonate (3×700 ml), water (2×700 ml) and brine (700 ml), then driedover magnesium sulphate. The solvent was evaporated to give crude(R)-5-trifluoromethyl-2-(2,3-epoxypropoxy)phenyl formate (16.7 g).

A mixture of the product from the previous reaction (16.7 g),tetrahydrofuran (220 ml) and a saturated aqueous potassium carbonatesolution (175 ml) was stirred vigorously at ambient temperature for 24hours. Water (500 ml) was added and the organic phase was removed. Theaqueous phase was extracted with ethyl acetate (3×300 ml) and thecombined organic extracts were dried over magnesium sulphate. Thesolvent was removed under reduced pressure and the residue purified byflash column chromatography on silica eluting with a 4:1 grading to 1:1mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate.Appropriate fractions were combined and the solvent was removed underreduced pressure to give(S)-7-trifluoromethyl-1,4-benzodioxan-2-ylmethanol (12 g) as a yellowoil.

A solution of 4-toluenesulphonyl chloride (9.6 g) in dichloromethane (60ml) was added dropwise to a solution the product from the previousreaction (10.7 g) and 4-dimethylaminopyridine (6.7 g) in dichloromethane(90 ml) between 0-5° C.

The mixture was stirred at ambient temperature for 4 hours then allowedto stand for 18 hours. The solution was washed with dilute hydrochloricacid (5M, 2×300 ml) dried over magnesium sulphate and the solvent wasremoved under reduced pressure to afford(R)-7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate(15.5 g) as a white solid.

A mixture of the product from the previous reaction (2 g),N-benzylidene-4-piperidylmethylamine (1 g), potassium carbonate (1.35g), and potassium iodide (10 mg) in acetonitrile (75 ml) was heated atreflux, with stirring, under nitrogen for 24 hours. The reaction wascooled, filtered and concentrated under reduced pressure to afford(S)-N-benzylidene-1-[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine(6.3 g) as a yellow viscous oil.

The crude product from the previous reaction was stirred in aqueouspotassium hydrogen sulphate solution (0.6 M; 36 ml) for 5 hours atambient temperature then left to stand for 18 hours. The solution waswashed with ether (2×50 ml), basified using aqueous sodium hydroxidesolution (5 M) then extracted with ether (3×100 ml). The combinedethereal layers were dried over magnesium sulphate and evaporated todryness to afford(S)-4-(aminomethyl)-1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)piperidine(0.87 g) as an orange oil.

A mixture of the product from the previous reaction (0.87 g),2,3-dichlorobenzenesulphonyl chloride (1.29 g), triethylamine (1.1 ml)and dichloromethane (40 ml) was stirred under nitrogen for 3 hours thenleft to stand for 18 hours. The solvent was removed under reducedpressure and the residue was purified by flash chromatography on silicagel eluting with a 40:1 mixture of dichloromethane and methanol to give(S)-(-)-2,3-dichloro-N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamideas a cream solid (0.72 g), m.p. 139-140° C., [α]_(D) ²² -36.7⁰ (c=0.18,MeOH).

EXAMPLES 15-39

General Procedure

Triethylamine (0.042 ml, 0.3 mmol) was added to a 2 ml screw-top vialcontaining a stock solution of(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine indichloromethane (0.1M, 1 ml, 0.1 mmol) and an arylsulphonyl chloride(0.2 mmol). The reaction vials were sealed with a screw-cap then stirredat ambient temperature for 66 hours. The cap was removed and the solventwas removed initially under a stream of nitrogen, then under reducedpressure at 40° C. The residues were redissolved in dichloromethane (1ml) and an aliquot (0.020 ml) removed and added to digol (2 ml). Thedigol solution was shaken until homogeneous and the mixture analysed inin vitro biological assays.

Each of the following compounds was prepared, by selecting theappropriate arylsulphonyl chloride, as a crude sample using the generalprocedure detailed above:

EXAMPLE 15(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitrobenzenesulphonamideEXAMPLE 16(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamideEXAMPLE 17(S)-2-Chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamideEXAMPLE 18(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-iodo-benzenesulphonamideEXAMPLE 19(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxy-2,3,6-trimethylbenzenesulphonamideEXAMPLE 20(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}naphth[2,1-d][1,2,3]oxadiazole-5-sulphonamide EXAMPLE 21(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4,6-trimethylbenzenesulphonamideEXAMPLE 22(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4,5,6-pentamethylbenzenesulphonamideEXAMPLE 23(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-(diethylamino)naphthalene-1-sulphonamideEXAMPLE 24(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamideEXAMPLE 25(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-nitrobenzenesulphonamideEXAMPLE 26(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methyl-3,5-dinitrobenzenesulphonamideEXAMPLE 27(S)-5-Chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxybenzenesulphonamideEXAMPLE 28(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-trifluoromethylbenzenesulphonamideEXAMPLE 29(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethoxybenzenesulphonamideEXAMPLE 30(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-naphthalenesulphonamideEXAMPLE 31(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-1-naphthalenesulphonamideEXAMPLE 32(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-dimethoxybenzenesulphonamideEXAMPLE 33(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methylbenzenesulphonamideEXAMPLE 34(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzene-sulphonamideEXAMPLE 35(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-fluoro-2-methylbenzenesulphonamideEXAMPLE 36(S)-2,5-Dibromo-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamideEXAMPLE 37(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-nitro-benzenesulphonamideEXAMPLE 38(S)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4-trifluorobenzenesulphonamideEXAMPLE 39(S)-2,5-Dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,6-difluorobenzenesulphonamide.EXAMPLES 40-49

General Procedure

Stock solutions of the appropriate starting amine of formula XVI indichloromethane (0.1 M, 0.3-0.8 ml, 0.03-0.08 mmol) and triethylamine indichloromethane (50% v/v, 3 equivalents) were added to a number of 2 mlscrew-top vials, each containing a different aryl sulphonyl chloride (2equivalents). This process was repeated for each of the 3 differentamines. The reaction vials were sealed then agitated on an orbitalshaker at ambient temperature for 14 hours. The caps were removed andthe solvent was allowed to evaporate under ambient conditions, thenunder reduced pressure at 40° C. The residues were redissolved indichloromethane to a standard concentration of 0.1 M then furtherdiluted to 10⁻³ M with digol. The digol solution was shaken untilhomogeneous and the mixture containing the active compound analysed inthe in vitro biological assays.

The following compounds were prepared in a single batch, as the majorcomponent in a mixture (purities indicated).

Examples 40-43 used(S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine,prepared as described in example 1 of WO97/03071, as the starting amine:

EXAMPLE 40 (S)-(-)-N-{[1-(7-Chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide, HPLC 56% (3.03min); m/z 455 (MH⁺). EXAMPLE 41(S)-(-)-2-Chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesutphonamide,HPLC 73% (3.14 min); m/z 471 (MH⁺). EXAMPLE 42(S)-(-)-3-Chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluoro-benzenesulphonamide,HPLC 62% (3.35 min); m/z 489 (MH+). EXAMPLE 43(S)-(-)-2,3-Dichloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide,HPLC 66% (3.39 min); m/z 505 (MH⁺).

Examples 43-47 used(S)-4-(aminomethyl)-1-(7-bromo-1,4-benzodioxan-2-ylmethyl)piperidine,prepared as in example 13 as the starting amine:

EXAMPLE 44(S)-(-)-4-Acetamido-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl}-4-piperidyl]methyl)benzenesulphonamide,HPLC 76% (2.74 min); m/z 538, 540 (MH⁺). EXAMPLE 45(S)-(-)-N-{[1-(7-Bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide,HPLC 50% (3.04 min); m/z 499, 501 (MH⁺). EXAMPLE 46(S)-(-)-N-{[1-(7-Bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-chlorobenzenesulphonamide,HPLC 83% (3.18 min); m/z 515, 517 (MH⁺). EXAMPLE 47(S)-(-)-N-{[1-(7-Bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamide,HPLC 88% (3.14 min); m/z 517, 519 (MH⁺). EXAMPLE 48(S)-(-)-3-Chloro-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide,HPLC 74% (3.39 min); m/z 533, 535, (MH⁺). EXAMPLE 49(S)-(-)-2,3-Dichloro-N-{[1-(⁶,⁷-methylenedioxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide,HPLC 71% (3.07 min); m/z 515 (MH⁺).

Example 49 used (S)-⁴-(aminomethyl)-1-(6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl)piperidine,prepared as described below, as the starting amine.

A mixture of (R)-6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl4-toluenesulphonate (2.0 g), N-benzylidene-4-piperidylmethylamine(1.11g), potassium carbonate (3.8 g), and potassium iodide (100 mg) inacetonitrile (50 ml) was heated at reflux, with stirring, under nitrogenfor 24 hours. The reaction was cooled, filtered and concentrated underreduced pressure₋₋ to afford(S)-N-benzylidene-1-[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine(6.3 g) as a gum.

The crude product from the previous reaction (6.3 g) was stirred inaqueous potassium hydrogen sulphate solution (1 M; 100 ml) for 14 hoursat ambient temperature. The solution was washed with ether (3×200 ml),basified using aqueous sodium hydroxide solution (5 M) then extractedwith dichloromethane (3×100 ml). The combined extracts were washed withwater (200 ml), dried over magnesium sulphate and evaporated to drynessto afford (S)-⁴-(aminomethyl)-1-6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl)piperidine(1.18 g), [α]_(D) ²³ -63.4° (c=0.4, MeOH). as a viscous oil.

Analytical conditions for examples 40 to 49 are as follows:

HPLC conditions--Peco C18 column, 3cm×3mm i.d.; 100% aqueous ammoniumacetate (0.1 M), adjusted to pH 4.55 with acetic acid, to 100%acetonitrile linear gradient in 5 minutes, 2 ml/min; wavelengthdetection band 250-320nm, 5 min detection time. Percent purity wasdetermined by integration of detectable peak areas.

Mass Spectrometric conditions--Atmospheric pressure chemical ionisation,150-500 Da mass detection range.

EXAMPLE 50

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term "active compound" denotes any compound ofthe invention but particularly any compound which is the final productof one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose are de-aggregated and blended. Themixture is filled into hard gelatin capsules, each capsule containing aunit dose or part of a unit dose of active compound.

b) Tablets

Tablets are prepared from the following ingredients.

    ______________________________________                                                       Parts by weight                                                ______________________________________                                        Active compound  10                                                             Lactose 190                                                                   Maize starch 22                                                               Polyvinylpyrrolidone 10                                                       Magnesium stearate  3                                                       ______________________________________                                    

The active compound, the lactose and some of the starch arede-aggregated, blended and the resulting mixture is granulated with asolution of the polyvinyl-pyrrolidone in ethanol. The dry granulate isblended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

Enteric Coated Tablets

Tablets are prepared by the method described in (b) above. The tabletsare enteric coated in a conventional manner using a solution of 20%cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of activecompound is incorporated in 1300 parts by weight of triglyceridesuppository base and the mixture formed into suppositories eachcontaining a therapeutically effective amount of active ingredient.

What is claimed is:
 1. Compounds of formula I ##STR21## includingenantiomers and pharmaceutically acceptable salts thereof in which bothA and B are --O--;g is 0, 1, 2, 3 or 4; R₁ represents an alkyl groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo; an alkoxy group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo; halo; 6,7-methylenedioxy optionallyC-substituted by one or two alkyl groups containing 1 to 3 carbon atoms;or an alkylthio group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo; the substituents represented by R₁being the same or different when g is 2, 3 or 4; R₂ is H, an alkyl groupcontaining 1 to 3 carbon atoms, or an alkoxy group containing 1 to 3carbon atoms; R₃ and R₄, which are the same or different, are H, or analkyl group containing 1 to 3 carbon atoms; U is an alkylene chaincontaining 1 to 3 carbon atoms, optionally substituted by one or morealkyl groups each containing 1 to 3 carbon atoms; Q represents adivalent group of formula IIc ##STR22## in which E and E' are bothethylene, V is methylene, and R₆ is H T represents phenyl, 1- or2-naphthyl, 5-naphth[2,1-d][1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-,4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2-,3- orquinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each ofwhich may be optionally substituted by one or more substituents selectedfrom a) halo, b) an alkyl group containing 1 to 4 carbon atomsoptionally substituted by one or more halo, c) an alkoxy groupcontaining 1 to 3 carbon atoms optionally substituted by one or morehalo, d) an alkylthio group containing 1 to 3 carbon atoms optionallysubstituted by one or more halo, e) hydroxy, f) an acyloxy groupcontaining 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) analkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonylgroup containing 2 to 6 carbon atoms, k) a carbamoyl group orcarbamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, I)a sulphamoyl orsulphamoylmethyl group each optionally N-substituted by one or two alkylgroups each containing 1 to 3 carbon atoms, m) an amino group optionallysubstituted by one or two alkyl groups each containing 1 to 5 carbonatoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido. 2.Compounds of formula I, as claimed in claim 1, in which A is --O--, B is--O--, g is 1, R₁ is preferably halo or an alkyl group containing 1 to 3carbon atoms optionally substituted by one or more halo, R₂ is H, R₃ andR₄ are both H, U is methylene, Q is a group of formula IIc in which Eand E' are both ethylene, V is methylene, R₆ is H, and T is 1-naphthyl,2-naphthyl, 5-naphth[2,1-d][1,2,3]oxadiazolyl, 2-pyridyl, 3-pyridyl,phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl,2,3,4,5,6-pentamethylphenyl, 2-fluorophenyl, 4-fluorophenyl,2,6-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl,2-chlorophenyl, 4-chlorophenyl, 2,5-dibromophenyl, 4-iodophenyl,2,5-dibromo-3,6-difluorophenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl,3,4-dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl,5-chloro-2-methoxyphenyl, 5-fluoro-2-methylphenyl,4-trifluoromethoxyphenyl, 2,5-bis(2,2,2-trifluoroethoxy)phenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-chloro-4-trifluoromethylphenyl, 4-acetamidophenyl, 2-nitrophenyl,3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl,4-methyl-3,5-dinitrophenyl, 5-(diethylamino)-1-naphthyl,2,3-dichlorophenyl or 3-chloro-4-fluorophenyl.
 3. Compounds of formulaI, as claimed in claim 1, selectedfrom:N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-sulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-nitrobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,4-dimethoxybenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamide;4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxybenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,6-difluorobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-chlorobenzenesulphonamide;N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-sulphonamideN-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3-dichlorobenzensulphonamide2,3-dichloro-N-{[1-(7-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamideN-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitrobenzenesulphonamideN-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamide2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamideN-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-dinitrobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}2,5-bis(2,2,2-trifluoroethoxy)benzenesulphonamide;2-chloro-N-{[1-(7-chloro-,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-iodobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methoxy-2,3,6-trimethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}naphth[2,1-d][1,2,3]-oxadiazole-5-sulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4,6-trimethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4,5,6-pentamethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-(diethylamino)naphthalene-1-sulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-nitrobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methyl-3,5-dinitrobenzenesulphonamide;5-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methoxybenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3-trifluoromethylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-trifluoromethoxybenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-naphthalenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-1-naphthalenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,5-dimethoxybenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-methylbenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-5-fluoro-2-methylbenzenesulphonamide;2.5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-nitrobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,3,4-trifluorobenzenesulphonamide;2,5-dibromo-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-3,6-difluorobenzenesulphonamide;N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;2-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;3-chloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide;2,3-dichloro-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;4-acetamido-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-benzenesulphonamide;N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-fluorobenzenesulphonamide;N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-chlorobenzenesulphonamide;N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2,4-difluorobenzenesulphonamide;3-chloro-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzenesulphonamide;2,3-dichloro-N-{[1-(6,7-methylenedioxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide;andpharmaceutically acceptable salts thereof in the form of individualenantiomers, racemates, or other mixtures of enantiomers.
 4. A method oftreating depression, anxiety, psychoses, tardive dyskinesia, Parkinson'sdisease, obesity, hypertension, Tourette's syndrome, sexual dysfunction,drug addiction, drug abuse, cognitive disorders, Alzheimer's disease,senile dementia, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders and anorexia, cardiovascular andcerebrovascular disorders, non-insulin dependent diabetes mellitus,hyperglycaemia, constipation, arrhythmia, disorders of theneuroendocrine system, stress, or spasticity in human beings, whichcomprises the administration of a therapeutically effective amount of acompound of formula I, as claimed in claim 1, to a patient in needthereof.
 5. A process for the preparation of compounds of formula I inwhich Q is a group of formula IIc, comprising the reaction of a compoundof formula XIV ##STR23## in which D' is H and m is 0, 1 or 2, with acompound of formula IV ##STR24## in which Z is a leaving group,optionally in the presence of a base, optionally in the presence of apresence of a suitable solvent, and optionally in the presence of acatalyst.
 6. A pharmaceutical composition comprising a compound offormula I, as claimed in claim 1 in conjunction with a pharmaceuticallyacceptable diluent or carrier.